We will test the hypothesis that the damaging effects associated with rat liver microsomal lipid peroxidation may be modified by replacing dietary (n-6) fatty acids with those of the (n-3) family. Two mechanisms by which such modifications may result will be explored; first, that the perioxidation of (n-3) fatty acids results in a group of specific oxidative products with less of an ability to cause injury than those derived from (n-6) fatty acid; and second, that (n-3) fatty acids inhibit phospholipase A-mediated fatty acyl release and by so doing alter the course of lipid peroxidation and the specific productis. The rational for the first mechanism is that specific toxic products of peroxidation, including notedly 4- hydroxynonenal, appear to require the (n-6) structure for their formation. The second (phospholipase) mechanism was derived from numerous studies demonstrating a strong association between lipid peroxidative events and enhanced phospholipase A activities as well as reports that dietary (n-3) fatty acids inhibit fatty acid release in platelets. Initial studeis will identify lipid peroxidative products derived from purified fatty acids using Overpressure-Layer Chromatography (OPLC) as well as HPLC and GC/MS. In parallel with these investigations we will assess the injurious effects of purified peroxidation products of (n-6) and (n- 3) fatty acid origin by measuring effects on enzyme activities and on lysosomal membrane integrity. The comparative effects of dietary (n-6) and (n-3)-fatty acids on lipid peroxidation will be assessed by feeding rats defined diets with varying proportions of corn oil ((n-6)-enriched) to menhaden oil ((n-3)-enriched) and measuring microsomal peroxidation products generated in vitro (by reduced iron) and in vivo (by CCL4). Effects of phospholipase A inhibition on microsomal lipid peroxidative products (in vitro) will be defined and compared with those formed following peroxidation of microsomes from menhaden oil-fed rats. Effects of the menhaden oil diet on microsomal phospholipase activity will also be defined. In view of the current interest in dietary (n- 3) fatty acids for the prevention of atherosclerosis, it is important to understand the effects of these compounds on lipid peroxidative injury, a potential aspect of numerous disease processes.